Within the context of this renewal application, project 1 focuses on the previously established connection between a variety of mouse models with genetic defects in nucleotide excision repair and the segmental progeroid phenotype exhibited by these mutants (and the corresponding human patients). Complementary to project 4, project 1 addresses the impact of helix-distorting DMA damage on onset, progression and type of ageing and how it triggers a 'survival' response that normally is associated with longevity. We identified this response recently by gene expression profiling. In the current proposal we would like to capitalize on the mouse mutants for addressing 3 specific aims. First, in collaboration with project 3 we intend to extract valuable biomarkers and extend these to the human condition (together with project 5). These will be invaluable for early detection and proper diagnosis of ageing-related pathology, which is essential for the design of effective prevention strategies, for accurate prognosis, and for monitoring modalities for intervention and therapy. The wide spectrum of ageing-associated diseases exhibited by our progeroid mice allows discovery of markers for many different ageing-related pathologies. Secondly, we plan to use the rapidly aging mutant mice and derived cell lines for the design of cellular reporter assays for the screening of intervention molecules that either alleviate the induction of DMA damage or improve the cellular and organismal response to it (e.g. trigger the 'survival' response). For this we will utilize the detailed gene expression profiling data we have collected that is specific for ageing pathology and the 'survival' response towards genotoxic stress and combine different elements of gene expression (transcription as well as microRNA-mediated regulatory elements) to obtain a maximal dynamic range for the assay. The final objective is to employ a novel knock-in mouse model expressing a fluorescent repair protein in all organs and tissues. In combination with sophisticated single cell repair assays we plan to use the mouse knock-in to examine whether or not DNA repair potency declines in ageing and if so how, whether it is stochastic (cf. project 2). Thus project 1 has multiple links with all other projects of the programme.